The torso response element binds GAGA and NTF-1/Elf-1, and regulates tailless by relief of repression.

Abstract

Modulation of transcription factor activity leading to changes in cell behavior (e.g., differentiation versus proliferation) is one of the critical outcomes of receptor tyrosine kinase (RTK) stimulation. In the early Drosophila embryo, activation of the torso (tor) RTK at the poles of the embryo activates a phosphorylation cascade that leads to the spatially specific transcription of the tailless (tll) gene. Our analysis of the tor response element (tot-RE} in the tll promoter indicates that the key activity modulated by the tor RTK pathway is a repressor present throughout the embryo. We have mapped the tor-RE to an ll-bp sequence; using this sequence as the basis for protein purification, we have determined that the proteins GAGA and NTF-1 (also known as Elf-l, product of the grainyhead gene) bind to the tot-RE. We demonstrate that NTF-1 can be phosphorylated by MAPK (mitogen-activated protein kinase), and that tll expression is expanded in embryos lacking maternal NTF-1 activity; these results make NTF-1 a likely target for modulation by the tor RTK pathway in vivo. The data presented here support a model in which activation of the tor RTK at the poles of the embryos leads to inactivation of the repressor and therefore, to transcriptional activation (by activators present throughout the embryo) of the tll gene at the poles of the embryo.[Key Words: Torso tyrosine kinase receptor; transcription factor; GAGA; NTF-1; Elf-l; tailless; Trithorax-like; grainyhead] Received June 20, 1995; revised version accepted October 24, 1995.A multitude of extracellular signals can lead to a change in the program of cellular gene activity. An important mechanism by which extracellular signals {growth factors) are transduced is by receptor tyrosine kinases (RTKs). Ligand stimulation of an RTK leads to activation of a series of proteins: Transient generation of Ras-GTP leads to activation of a cascade of serine-threonine kinases in the order Raf-1, mitogen-associated protein (MAP) kinase kinase (MAPKK), and MAP kinase {MAPK) (for review, see Hill and Treisman 1995). This "cassette" of sequentially acting proteins functions in mammalian cultured cells in the platelet-derived growth factor (PDGF), epidermal growth factor (EGF), and nerve growth factor (NGFI activated pathways, in Drosophila in the sevenless and torso receptor-activated pathways, and in nematodes in the Let-23 (an EGF receptor homolog)-activated pathway (for review, see Perrimon 1993).Modification of the transcriptional program resulting from RTK activation can be ascribed, at least in part, to the function of activated MAPK in phosphorylating vat4Corresponding author.ious ets family transcription factors (for review, see Hill and Treisman 1995). Although our understanding of the cassette of proteins involved in the phosphorylation cascade is fairly robust, the subsequent steps that ultimately lead to altered cell behavior are less well defined. Neither all of the transcription factors modulated, nor all of the genes targeted by any one activated RTK are known.T...

Identification and characterization of Grainyhead‐like epithelial transactivator (GET‐1), a novel mammalian Grainyhead‐like factor

“…Drosophila Grainyhead and mammalian Grainyhead-related transcription factors have been shown to both activate and repress transcription Huang et al, 1995;Liaw et al, 1995;Hayashi et al, 1999;Huang and Miller, 2000;Rodda et al, 2001). To map potential transactivation domains in GET-1, regions of the protein were expressed as fusions with the GAL-4 DNA-binding domain.…”

“…Several other genes involved in epidermal development may also be targets of Grainyhead, including Ultrabithorax, Engrailed, and Fushi tarazu (Dynlacht et al, 1989). In addition to stimulating gene expression, Grainyhead may also act as a transcriptional repressor, restricting expression of tailless and decapentaplegic to particular domains in the early fly embryo Liaw et al, 1995).…”

Drosophila female sterile (1) homeotic is a multifunctional transcriptional regulator that is modulated by Ras signaling

“…Removal of Tor or any other member of its signaling cascade (the "Terminal Group") results in loss of tll (and hkb) expression. Tor signaling activates tll by relieving repression caused by at least three transcription factors: Groucho (Gro; Paroush et al, 1997), Capicua (Cic; Jimenez et al, 2000), and possibly Grainy-head (Grh; Liaw et al, 1995). Overexpression of tor or loss of any of these repressors causes ectopic expression of tll throughout the animal.…”

Phosphorylation of Grainy head by ERK is essential for wound-dependent regeneration but not for development of an epidermal barrier

“…1A). High-affinity DNA binding of GRH requires homodimerization and induces activation or repression of GRH-dependent target gene transcription (17,19,20). However, we still have very limited information on how the transcriptional activity of GRH is regulated in cells and organisms.…”

“…From this result, we inferred that ERK is in the signaling pathway from injury to activation of GRH-dependent wound enhancers. It was shown that GRH activity is controlled by the Breathless Receptor Tyrosine Kinase in the embryonic trachea (23) and that GRH can be phosphorylated by ERK in vitro (20). However, there has been a lack of evidence supporting a direct relationship between ERK and GRH in late embryonic epidermal tissue and the physiological importance of GRH phosphorylation in epidermal barrier generation and regeneration.…”